Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:26]3[CH:31]=[C:30]([CH3:32])[C:29]([O:33][CH3:34])=[C:28]([CH3:35])[CH:27]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:9]2=[O:25])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl.C(OCC)(=O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]([S:46]([CH3:45])(=[O:48])=[O:47])[S:46]([CH3:45])(=[O:48])=[O:47])=[CH:3][CH:4]=2)([C:26]2[CH:27]=[C:28]([CH3:35])[C:29]([O:33][CH3:34])=[C:30]([CH3:32])[CH:31]=2)[C:9]1=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(C)cc(C2(c3ccc(N)cc3)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1c(C)cc(C2(c3ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc3)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc1C
Reaction time: 2 h
Yield: 182.1 %

Procedure:
Combine 3-(4-amino-phenyl)-1-(2-chloro-benzyl)-3-(4-methoxy-3,5-dimethyl-phenyl)-1,3-dihydro-indol-2-one (73 mg, 0.15 mmol), N,N-diisopropylethylamine (0.040 mL, 0.23 mmol) and methanesulfonyl chloride (0.013 mL, 0.165 mmol) in CH2Cl2 (1 mL). After 5 h. stirring at room temperature TIC (50% EtOAc/hexanes) shows reaction not complete. Add more N,N-diisopropylethylamine (0.040 mL, 0.23 mmol) and methanesulfonyl chloride (0.013 mL, 0.165 mmol) and stir 2 h. more at which time reaction complete. Dilute with ethyl acetate and wash with water amd brine. Dry (MgSO4), filter and concentrate in vacuo to give 96 mg of a residue. Purify by radial chromatography (step gradient of 10% EtOAc/hexanes, 20% EtOAc/hexanes, 25% EtOAc/hexanes and 33% EtOAc/hexanes to obtain 56 mg (58%) of the title compound. MS (ES): m/z=639 (M+1); 1H NMR(DMSO-d6); δ7.54-7.45 (m, 4H), 7.37-7.22 (m, 5H), 7.15 (t, J=7.5, 1H), 7.00 (m, 2H), 6.87 (s, 2H), 5.09 (s, 2H), 3.64 (s, 3H), 3.53 (s, 6H), 2.17 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[OH:19])[NH2:15].[OH-].[K+]>O>[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12)[NH2:15]
Reactant: Clc1ccnc2[nH]ccc12
Reactant: Nc1ccc(O)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 25 °C

Procedure:
543 mg (3.56 mmol) of 4-chloro-1H-pyrrolo[2,3-b]pyridine (from example XVIII, 905 mg (7.12 mmol) of 3-fluoro-4-hydroxyaniline and 399 mg (7.12 mmol) of powdered potassium hydroxide are heated at 260° C. for 8 hours. Another 905 mg (7.12 mmol) of 3-fluoro-4-hydroxyaniline and 200 mg (3.56 mmol) of powdered potassium hydroxide are added, and the mixture is reacted at 260° C. for another 8 h. For work-up, the mixture is cooled to room temperature, diluted with water and extracted three times with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated using a rotary evaporator. The residue is purified by preparative HPLC. The fractions which, according to LC-MS, contain 39% of product are used without further purification for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[CH:21]=[C:14]3[C:15](Cl)=[N:16][CH:17]=[C:18]([F:19])[C:13]3=[N:12]2)=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].[Br:22][Si](C)(C)C>C(#N)CC>[Br:22][C:15]1[C:14]2=[CH:21][N:11]([C:3]3[C:2]([Cl:1])=[CH:9][C:8]([F:10])=[CH:7][C:4]=3[C:5]#[N:6])[N:12]=[C:13]2[C:18]([F:19])=[CH:17][N:16]=1
Reactant: N#Cc1cc(F)cc(Cl)c1-n1cc2c(Cl)ncc(F)c2n1
Reactant: C[Si](C)(C)Br
Solvent: CCC#N
Product: N#Cc1cc(F)cc(Cl)c1-n1cc2c(Br)ncc(F)c2n1
Temperature: 80 °C
Yield: 99.9 %

Procedure:
3-Chloro-2-(4-chloro-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-5-fluorobenzonitrile (735 mg, 2.26 mmol) was suspended in propionitrile (44 mL), under an atmosphere of nitrogen and bromotrimethylsilane (0.82 mL, 5.64 mmol) was added. The reaction mixture was heated at 80° C. for 5 hours. The resultant mixture was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a beige solid (834 mg, 100% yield). 1H NMR (300 MHz, CDCl3): δ 8.38 (d, J=2.3 Hz, 1H), 8.03 (d, J=3.0 Hz, 1H), 7.65 (dd, J=7.6, 2.8 Hz, 1H), 7.56 (dd, J=7.0, 2.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Li]CCCC.CCCCCC.[S:20](=[O:22])=[O:21].C1C(=O)N([Cl:30])C(=O)C1>C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:20]([Cl:30])(=[O:22])=[O:21]
Reactant: Fc1cccc(F)c1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=S=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=S(=O)(Cl)c1c(F)cccc1F
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a cooled solution of 1,3-difluorobenzene (9.4 g, 82 mmol) in diethyl ether (120 mL) was added n-BuLi in hexane (32.3 mL, 81 mmol) dropwise at −78° C. The reaction mixture was stirred at −78° C. for 3 h. Sulfur dioxide (106 g, 1648 mmol) was flushed into the solution and stirred at −60° C. for 20 mins, which produced a white solid. NCS (12.10 g, 91 mmol) was added and the reaction mixture was warmed to rt and for 1 h. The reaction mixture with white solid changed to pale brown solution. The reaction mixture was filtered and concentrated to give crude 2,6-difluorobenzenesulfonyl chloride, which was added dropwise into methyl 3-amino-2-fluorobenzoate (5.19 g, 30.7 mmol) in pyridine (50 mL) at 15° C. After the addition, the reaction mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction mixture and then followed by 40 mL of cold water. The mixture was heated to 55° C. with stirring until all red solids dissolved. The upper layer was organic layer which was isolated and washed again with water. The organic layer was dried and evaporated under reduced pressure. Petro ether was added to the crude product and heated to reflux and then cooled to 5° C. The solids were filtered and rinsed with petro ether to afford methyl 3-(2,6-difluorophenylsulfonamido)-2-fluorobenzoate (6.91 g, 10.35 mmol, 12.56% yield) as orange solid. LCMS: [M+NH4]+=363.0.
Reaction SMILES: [C:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([C:15](=[O:18])[CH2:16][Br:17])[CH:11]=[CH:12][C:13]=1[Cl:14])(=[O:7])=[O:6])(=[O:3])[CH3:2].[CH3:19][NH:20][C:21]([NH:23][CH3:24])=[S:22]>C(O)C.CC(C)=O>[BrH:17].[C:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([C:15]2([OH:18])[CH2:16][S:22][C:21](=[N:20][CH3:19])[N:23]2[CH3:24])[CH:11]=[CH:12][C:13]=1[Cl:14])(=[O:7])=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Reactant: CNC(=S)NC
Solvent: CCO
Solvent: CC(C)=O
Product: Br
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NC(C)=O)c2)N1C
Reaction time: 8 h

Procedure:
10.5 g of 3'-acetylsulfamoyl-2-bromo-4'-chloro-acetophenone are dissolved in 100 ml of ethanol and heated to 45°-50° C during 5 minutes after the addition of 3 g of 1,3-dimethyl thiourea. After standing overnight at 20° C the solvent is expelled under reduced pressure, the residue is dissolved in acetone and the product is precipitated with diisopropyl ether while stirring.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[OH:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:27][O:26][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][C:21]=1[O:24][CH3:25])[N:4]=[C:3]([CH2:2][O:32][C:33]1[N:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=1)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:10]1[CH:5]=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: Cc1cccc(O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(COc2cccc(C)n2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
A mixture of ethyl 2-chloromethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl)quinoline-3-carboxylate (1.5 g), 2-hydroxy-6-methylpyridine (0.4 g), potassium carbonate (0.511 g) and N,N-dimethylformamide (20 ml) was stirred at 120° C. for 2 hours. Then the mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and the solvent was distilled off. The residual oil was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate, ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)- 2-[(2-methyl-6-pyridyl)oxymethyl]quinoline-3-carboxylate (0.79 g, 46%) was obtained and recrystallized from chloroform/hexane.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]([N:12]([CH2:17][CH3:18])[S:13]([CH3:16])(=[O:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:19])[CH:8]=2)[O:3]1.[H-].[Na+].Cl.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:32]Cl)[CH:27]=1>CC(N(C)C)=O>[CH2:17]([N:12]([CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:19][CH2:32][C:28]3[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=[CH:30][N:29]=3)[CH:8]=2)[O:3][C:2]([CH3:1])([CH3:20])[CH2:11]1)[S:13]([CH3:16])(=[O:15])=[O:14])[CH3:18]
Reactant: COc1ccnc(CCl)c1
Reactant: CCN(C1CC(C)(C)Oc2ccc(O)cc21)S(C)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCN(C1CC(C)(C)Oc2ccc(OCc3cc(OC)ccn3)cc21)S(C)(=O)=O
Temperature: 75 °C

Procedure:
0.58 g (1.9 mmol) of N-[2,2-dimethyl-6-hydroxychroman-4-yl]-N-ethyl-methanesulfonamide (Example 1g) was stirred at 50° C. for 30 min with 0.15 g (5 mmol) of NaH (80%) in 40 ml of DMA. A solution of 0.4 g (2 mmol) of 4-methoxy-2-chloromethylpyridine hydrochloride in 5 ml of DMA was then added dropwise and the mixture was heated to 75° C. for 2 h. After reaction was complete, it was concentrated in vac., the residue was treated with ice water, the mixture was extracted with EA, the extract was dried and concentrated, and the residue was crystallized using diisopropyl ether. 0.5 g was obtained, m.p. 87-89° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][OH:28].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:25][CH2:26][CH2:27][OH:28]
Reactant: OCCCBr
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.9 %

Procedure:
A stirred solution of 10.1 grams (0.038 mole) of 2,6-dichloro-4-(phenylmethoxy)phenol (known compound) and 8.0 grams (0.058 mole) of potassium carbonate in 150 mL of DMF was cooled to 0–4° C. and 3.7 mL (0.041 mole) of 3-bromopropan-1-ol was slowly added. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it was stirred during an 18 hour period. After this time water was added to the reaction mixture, and the mixture was extracted with two 150 mL portions of diethyl ether. The combined extracts were dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 11.8 grams of residual solid. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH:9]1[C:14](/[CH:15]=[N:16]/[OH:17])=[CH:13][CH:12]=[C:11]([F:18])[CH:10]=1.[C:19]([O:22][CH2:23][C:24]#[CH:25])(=[O:21])[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[C:19]([O:22][CH2:23][C:24]1[O:17][N:16]=[C:15]([C:14]2[CH:13]=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)[CH:25]=1)(=[O:21])[CH3:20]
Reactant: O/N=C/c1ccc(F)cc1
Reactant: C#CCOC(C)=O
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1cc(-c2ccc(F)cc2)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-chlorosuccinimide (0.53 g, 4.00 mmol) in methylene chloride (20 mL) was added syn-4-fluorobenzaldoxime (0.56 g, 4.00 mmol) in one portion. The resulting mixture was stirred at room temperature for 3 hours. Propargyl acetate (0.10 g, 1.00 mmol) was then added in one portion, followed by triethylamine (0.28 mL, 2.00 mmol) in methylene chloride (5 mL) over a period of 20 min. The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was purified by prep-TLC (ethyl acetate:hexanes=1:4) to give [3-(4-fluorophenyl)isoxazol-5-yl]methyl acetate.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[F:6][C:7]([F:18])([F:17])[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12].Cl>CC#N.[OH-].[Na+]>[F:6][C:7]([F:17])([F:18])[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:12]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To a rapid stirring solution of glycine (15.014 g, 0.20 mol) in MeCN (400 mL) and 2 M NaOH (250 mL) at 0° C. was slowly added a solution of 3-(trifluoromethyl)-benzoyl chloride (41.714 g, 0.20 mol) in 75 mL of MeCN over 30 min. The cloudy yellow solution was stirred at 0° C. for 30 min. The reaction mixture was acidified with 3 M HCl to pH=3, followed by removal of MeCN on rotary evaporator. The resulting mixture was then extracted with EtOAc (400 mL×3). The combined organic layers were dried, filtered and concentrated to give a light yellow solid (48.53 g), which was triturated with toluene (500 mL). After filtration, the solid product was washed with cold toluene until the filtrate was colorless. After dried under high vacuum over the weekend, a white powder product: 44.60 g (90%) was afforded. MS (M+H+)=248.1. 1H NMR (DMSO-d6) δ 12.70 (br s, 1H), 9.17 (m, 1H), 8.20 (dd, 2H), 7.94 (dd, 1H), 7.78 (m, 1H), 3.97 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:30]=[CH:31][CH:32]=1)[CH2:15][NH:16][C:17]1[C:26]2[C:21](=[C:22]([C:27]([NH2:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][N:18]=1.C(N(CC)CC)C.CCOCC>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:13]=[C:14]([CH:30]=[CH:31][CH:32]=2)[CH2:15][NH:16][C:17]2[C:26]3[C:21](=[C:22]([C:27]([NH2:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc2c(NCc3cccc(NC(=O)c4ccc(F)cc4)c3)ncnc12
Reaction time: 8 h
Yield: 77 %

Procedure:
4-fluorobenzoyl chloride (240 μL, 0.5 M in anhydrous DCM, 0.11 mmol, 1.1 equiv.) was added to a solution of 4-[(3-aminobenzyl)amino]quinazoline-8-carboxamide (32 mg, 0.1 mmol, 1.0 equiv.) and triethylamine (40 μL, 0.3 mmol, 3.0 equiv.) in anhydrous DCM (2 mL). The resulting mixture was stirred at it overnight. Ether (2 mL) was added. The precipitate was filtered, washed with ether and DCM to yield the title compound in 77% yield. Mass: M+H+: 416.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.O.[N:10]([C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15])=[N+:11]=[N-:12].[OH-].[Na+]>O1CCOCC1>[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:14](=[O:15])[C:13]([N:10]=[N+:11]=[N-:12])([CH3:18])[CH3:17])[CH2:5][CH2:4]1
Reactant: CC(C)(N=[N+]=[N-])C(=O)Cl
Reactant: OCC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(N=[N+]=[N-])C(=O)N1CCC(CO)CC1

Procedure:
15 g. (0.13 mole) 4-Hydroxymethylpiperidine are dissolved in 130 ml. water and 30 ml. dioxan and 19.4 g. (0.13 mole) 2-azido-2-methylpropionic acid chloride (according to analogous literature: J.A.C.S., 77, 112/1955) added dropwise thereto. The pH of the solution is kept at 12 to 12.5 by the simultaneous dropwise addition of 2N aqueous sodium hydroxide solution. After ending of the reaction, the reaction mixture is extracted with diethyl ether. After drying with anhydrous sodium sulphate and evaporating, there are obtained 17.8 g. of crude oil, i.e. 60% of theory, which can be used in the next step without further purification.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:49]=[C:50]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[CH:51]=1)[CH2:10][N:11]([CH:46]1[CH2:48][CH2:47]1)[C:12]([C@@H:14]1[C@@H:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]3[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=3[Cl:38])=[CH:22][CH:21]=2)[CH2:18][CH2:17][N:16]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:15]1)=[O:13])#[N:2].C([Sn]([N:70]=[N+:71]=[N-:72])(CCCC)CCCC)CCC>O1CCOCC1.CCOC(C)=O>[CH:46]1([N:11]([CH2:10][C:9]2[CH:8]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][C:1]3[N:70]=[N:71][NH:72][N:2]=3)[CH:51]=[C:50]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[CH:49]=2)[C:12]([C@@H:14]2[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]4[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=4[Cl:38])=[CH:22][CH:21]=3)[CH2:18][CH2:17][N:16]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[CH2:15]2)=[O:13])[CH2:48][CH2:47]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCC#N)c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCc2nn[nH]n2)c1
Temperature: 150 °C

Procedure:
To a solution of tert-butyl (3R,4S)-3-{[[3-(3-cyanopropoxy)-5-(3-methoxy-propyl)benzyl](cyclopropyl)amino]carbonyl}-4-{4-[2-(2,6-dichloro-4-methylphen-oxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from the previous step in dioxane (0.17 M) was added tri-n-butyltin azide (3 eq.). The reaction was heated to 150° C. in a sealed tube for 18 h. After cooling down to rt, the reaction was diluted with EtOAc. The organic extract was washed with saturated aqueous NH4Cl solution, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, first 50% EtOAc in Hex to 100% EtOAc, then 5% MeOH in DCM) to afford the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH3:17])[C:5]([O:7]CCC)=[O:6].O.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH3:17])[C:5]([OH:7])=[O:6]
Reactant: CCCOC(=O)c1ccc(OCCC)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCOc1ccc(C(=O)O)cc1C
Temperature: 0 °C
Yield: 84 %

Procedure:
The crude propyl 3-methyl-4-propoxybenzoate was dissolved in methanol (25 mL) and water (50 mL) and treated with solid sodium hydroxide (31.6 g, 789 mmol). The reaction mixture was refluxed for 1 h. The reaction mixture cooled to 0° C. and acidified with 12 M HCl (74 mL, 890 mmol). The resulting solid filtered to provide 3-methyl-4-propoxy-benzoic acid (3.22 g, 16.6 mmol, 84%) as a light pink solid. ESI-MS m/z calc. 194.0943. Found 195.3 (M+1)+; Retention time: 1.41 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 7.77 (dd, J=8.5, 2.2 Hz, 1H), 7.73 (d, J=1.4 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 4.01 (t, J=6.4 Hz, 2H), 2.18 (s, 3H), 1.82-1.69 (m, 2H), 1.01 (t, J=7.4 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1.[H-].[Na+].[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].O>CN(C)C=O>[Si:20]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(OCCO)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCOc1ccc([N+](=O)[O-])cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 40.5 %

Procedure:
2-(2-Hydroxyethoxy)-5-nitropyridine (obtained as described in Annalen der Chemie., 1936, 521, 286) (114 g) was added portionwise to an ice-cooled, stirred suspension of sodium hydride (60% dispersion in mineral oil; 24.8 g) in N,N-dimethylformamide (DMF) (600 ml), at such a rate that the temperature did not exceed 10° C. The solution was stirred at 0° C. for 10 minutes, and then tert-butylchlorodiphenylsilane (171 g) was added dropwise at such a rate that the temperature did not exceed 10° C. The solution was stirred for 72 hours and then added to water (2 l). The mixture was extracted with ethyl acetate (2 ×1 l), and the extracts were washed with water (1 l) and saturated sodium chloride solution (500 ml), and then dried (MgSO4). Volatile material was removed by evaporation, and the residue was purified by flash chromatography, eluting with hexane to give 2-[2-(t-butyldiphenylsilyl)oxyethoxy]-5-nitropyridine (B) (106 g), as an oil which solidified on standing, m.p. 63°-64° C. (from hexane); NMR (d6 -DMSO): 1.0(s,9H), 4.0(t,2H), 4.55(t,2H), 7.0(d,1H), 7.3-7.5(m,6H), 7.55-7.75(m,4H), 8.45(dd,1H), 9.0(d,1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=1)[CH2:27][NH:28][C:29](=[O:31])[CH3:30]>>[C:29]([NH:28][CH2:27][C:26]1[CH:25]=[C:24]([NH:23][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])[CH:34]=[CH:33][CH:32]=1)(=[O:31])[CH3:30]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CC(=O)NCc1cccc(N)c1
Product: CC(=O)NCc1cccc(NC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)c1

Procedure:
N-[3-(Acetylaminomethyl)phenyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and N-(3-aminobenzyl)acetamide using method J. NMR; δH [2H6]—DMSO 10.34,(1H, b), 8.38,(1H, t), 8.06,(2H, d), 7.91,(1H, dd), 7.79,(1H, d), 7.70,(2H, m), 7.57,(3H, m), 7.30,(1H, t), 7.00,(1H, d), 4.25,(2H, d), 2.57,(3H, s), 2.34,(3H, s), 1.88,(3H, s). LCMS; retention time 3.07 min, MH+ 441.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][N:8]=1)=[O:5])[CH3:2].I[C:23]1[CH:24]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[C:26](=[O:29])[NH:27][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[N:8]=[CH:9][C:10]([C:23]2[CH:24]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[C:26](=[O:29])[NH:27][CH:28]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: COC(=O)c1cc(I)c[nH]c1=O
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1ccc(-c2c[nH]c(=O)c(C(=O)OC)c2)cn1
Temperature: 25 °C

Procedure:
A solution of N-ethyl-N′-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea (Intermediate 1, 200 mg, 0.69 mmol), methyl 5-iodo-2-oxo-1,2-dihydro-3-pyridinecarboxylate (174 mg, 0.62 mmol), Tetrakispalladium (72.2 mg, 0.06 mmol), and cesium carbonate (224 mg, 0.69 mmol) in dioxane (4 mL) and water (1.000 mL) was heated to 100° C. in microwave for 1 h. The reaction mixture was filtered through Celite and washed with methanol. The resulting solution was concentrated under reduced pressure to give a yellow solid. The solid was triturated with acetone, then collected by filtration and added to hot acetone/water. The solution was cooled to room temperature, and the solid that formed was collected by filtration and placed under high vacuum to remove residual solvent (58 mg). MS (ESP): 317 (M+H+) for C15H16N4O4.